In recent years, the presence of cancer stem cells in several types of cancers such as brain tumor (see Non Patent Literatures 1 to 4) and colon cancer (see Non Patent Literatures 5 to 9) has been reported. Cancer stem cells are defined as a small number of cells among cancer cells that constitute cancer, which have the properties of stem cells and have an ability to form a tumor. Cancer stem cells have the following characteristics: 1) a low division rate and a low replication rate; 2) a high self-replicating and self-repairing ability; 3) the cancer stem cells produce a large number of cancer cells around themselves as a result of differentiation, while maintaining themselves by self-replication in cancer tissues; 4) resistance to anticancer agents and resistance to radiotherapy (see Non Patent Literatures 4, 10 and 11). However, it is not essential for cancer stem cells to have all of the properties 1) to 4), if the cancer stem cells have the properties of stem-like cells. It is important that such a cancer stem cell is a main cause of the malignancy of cancer. Thus, the cancer stem cell is also referred to as a “tumor-initiating cell” or a “cancer-initiating cell” (a cancer initiating cell, or an initiating cell of tumor or cancer) (see Non Patent Literature 12).
A cancer stem cell has attracted attention as an important therapeutic target in treatment of cancer. The cancer stem cell hypothesis had already been proposed in the 1970s. In recent years, it has also been elucidated that the presence of cancer stem cells is associated with the resistance to various types of therapy, recurrence, and malignant alteration of cancer. However, a main body of such cancer stem cells remains unknown, and currently, there has been little progress in the study regarding biological analyses and cancer treatments (in particular, cancer stem cell-specific treatments) that target cancer stem cells.
For solid cancer, in particular, brain tumor, CD133 has been reported as a cancer stem cell marker that is expressed on the cell surface (see Non Patent Literatures 1 to 4). Human CD133 was confirmed to be an epitope expressed in CD34+ hematopoietic stem cells in 1997 (see Non Patent Literature 13). CD133 is a five-transmembrane type membrane glycoprotein that is also referred to as prominin 1 (PROM 1), and it includes many spliced isoforms and the expression thereof depends on tissues. A CD133 ligand and a signal downstream thereof have not yet been reported, and the functions thereof have been unknown. It has been reported that CD133 is a marker for hematopoietic progenitor cells and vascular endothelial progenitor cells, and at the same time, CD133 is a cancer stem cell marker for brain tumor (see Non Patent Literatures 1 to 4), prostate cancer (see Non Patent Literature 14), colon cancer (see Non Patent Literatures 5 to 9), lung cancer (see Non Patent Literature 15), and hepatic cancer (see Non Patent Literatures 16 to 18).
It has been reported that CD133 is expressed in a tissue-dependent manner by at least 5 types of promoters. It has been demonstrated that promoters 1 and 2 had activity while promoters 3 to 5 did not have particularly high activity as a result of a reporter assay in which the human colon carcinoma cell line Caco-2 cell and the human teratocarcinoma cell line NT-2 were used (see Non Patent Literature 19). On the other hand, it has been reported that promoters 1 to 4 had almost no activity, and that promoter 5 had activity as a result of the analysis of the activity of CD133 promoters in the human colon carcinoma cell line Caco-2 and the human synovial sarcoma cell line Fuji (see Non Patent Literature 20). In these reports, all of the methods use a pGL3 enhancer vector, which means the activity of the CD133 promoter was enhanced by the enhancer, nevertheless relatively high promoter activity was not observed. Especially, despite it has been known that the Caco-2 cells strongly express CD133, it has also been known that the promoter activity of CD133 (in particular, promoters 1 to 4) is not so high even in a case in which the Caco-2 cells are used with the pGL3 enhancer vector. Moreover, the activity of CD133 promoters in cancer stem cells has not yet been known so far.
It has been generally known that promoters which are specific to tissues or cells such as stem cells have extremely lower activities than the constitutively and ubiquitously active promoters which are widely used infor inducing transgene expression, such as RSV promoter, CMV promoter or CA promoter. In using such tissue/cell-specific promoters for treatment or diagnosis, in many cases these promoters by themselves cannot be used for the treatment or the diagnosis due to its low promoter activity in cells of interest, and thus, it has been recognized that a means to enhance the promoter activity is necessary (see Patent Literature 1 and Non Patent Literature 21).
Virus vectors that are able to replicate specifically in cancer (conditionally replicating viruses: CRA) have been known, such as viral vector an adenoviral vector which lack the Rb-binding region in the E1 region (E1AΔ24) or which lack the p53-binding region in the E1 region (E1BΔ55), and an adenoviral vector in which an endogenous promoter of an E1 gene is substituted with a promoter that highly express specifically in cancer. Examples of the latter viral vector that has been reported include an adenoviral vector employing a urokinase-type plasminogen activation receptor promoter (see Patent Literature 2), an adenoviral vector employing a PEG3 promoter (see Patent Literature 3), and an adenoviral vector employing a survivin promoter (see Patent Literature 4). Since a cancer specific replicating adenoviral vector has oncolytic properties (see Non Patent Literature 22), it is considered to be effective for the treatment of cancer. Moreover, once viruses are infected/transfected in some cancer cells upon administration of the viral vector, they are amplified in the cancer cells, viral vectordestroy the cancer cells, and are further infected/transfected to peripheral or distant cancer cells. Accordingly, by loading a gene, CRA is also considered to be a useful tool for gene delivery. Furthermore, treatment with a viral vector targeting cancer stem cells has also been reported (Patent Literature 23).